Deciphering Genomic Complexity of Multiple Myeloma Using Optimized Optical Genome MappingGuermouche, Roynard, Servoli
et alJ Mol Diagn (2025) 27 (4), 306-322
Abstract: The genomic evaluation of multiple myeloma in routine diagnostics involves isolating plasma cells expressing CD138, usually followed by fluorescence in situ hybridization analyses. However, cell sorting often yields a limited number of cells, restricting the number of probes that can be used and limiting the analysis to a few markers required for minimal prognostic classification. Optical genome mapping is a high-resolution technology capable of identifying structural variants and copy number variations across the entire genome; however, it currently requires 1 million cells. To overcome this constraint, an innovative strategy was implemented in this work based on mixing CD138-positive and CD138-negative fractions from the same patient, optimizing the use of available CD138-positive cells for genome-wide analysis. First, dilution experiments demonstrated that a 50% CD138-positive mix was sufficient to achieve complete detection of clonal structural and copy number variants, while establishing a detection threshold of 24% for copy number variants. Using this optimized protocol, 13 additional samples from 13 patients were analyzed. Optical genome mapping achieved 93% (13/15) concordance with fluorescence in situ hybridization for clonal anomalies and revealed >22 additional genomic variations not detected by fluorescence in situ hybridization. This strategy consolidated multiple analyses into a single test, minimized material requirements, and addressed critical prognostic and increasingly described anomalies, providing refined stratification for patients with multiple myeloma.Copyright © 2025 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
The Association Between Dysglycemia and Endotheliopathy in ICU Patients With and Without Diabetes: A Cohort StudyGantzel Nielsen, Olsen, Lommer Kristensen
et alCrit Care Explor (2025) 7 (4), e1229
Abstract: Dysglycemia in critically ill patients is associated with endotheliopathy. This relationship may be altered in patients with diabetes.Dysglycemia is common in critically ill patients and associated with increased mortality. Endotheliopathy is thought to play a role in this relationship; however, evidence is scarce. The aim of this study was to investigate the associations between dysglycemia and endotheliopathy to inform future glycemic management.This prospective observational study included 577 acutely admitted adult ICU patients at Copenhagen University Hospital-North Zealand, Denmark.Up to twenty-four hours of patient glycemia was paired with same-day levels of endothelial biomarkers measured after each 24-hour period for three consecutive days. Endotheliopathy was assessed by measurement of Syndecan-1, Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), and soluble thrombomodulin (sTM).Of the included patients, a total 57.5% were males, median age was 71 yr (interquartile range [IQR], 63-79), and 24.6% had diabetes prior to admission. Median admission time was 5 d (IQR, 3-10). Time above range (TAR) greater than 13.9 mmol/L, but not TAR 10.0-13.9 mmol/L, was associated with increase in sTM (0.01 ng/mL per %-point increase in TAR, p = 0.049) and PECAM-1 (0.01 ng/mL per %-point increase, p = 0.007). Glycemic variability was associated with increases in sTM (0.24 ng/mL per mmol/L increase in sd, p = 0.001 and 0.03 ng/mL per %-point increase in coefficient of variation, p < 0.001). Hypoglycemia 3.0-3.9 mmol/L was associated with increases in sTM (3.0 ng/mL, p < 0.001) and PECAM-1 (1.54 ng/mL, p < 0.001).In acutely admitted adult ICU patients, hypoglycemia was associated with endotheliopathy regardless of preadmission diabetes status. Hyperglycemia and high glycemic variability were associated with endotheliopathy in patients without diabetes. This suggests different responses to acute dysglycemia in patients with and without diabetes and warrants further investigation in clinical trials.Copyright © 2025 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.
Entinostat, a histone deacetylase inhibitor, enhances CAR-NK cell anti-tumor activity by sustaining CAR expressionJo, Kaczmarek, Khan
et alFront Immunol (2025) 16, 1533044
Abstract: Allogeneic natural killer (NK) cell therapy has demonstrated significant potential in cancer immunotherapy by harnessing NK cells to target malignancies. CD138-targeting chimeric antigen receptor (CAR)-engineered NK cells offer a promising therapeutic option for multiple myeloma (MM). However, sustaining CAR expression on CAR-NK cells during ex vivo expansion poses a challenge to developing effective immunotherapies. In this study, primary NK cells were isolated, cryopreserved, and modified to express anti-CD138 CARs through retroviral transduction. Histone deacetylase inhibitors (HDACi), particularly entinostat (ENT), were applied to enhance CAR expression stability in CAR-NK cells. Our findings indicate that ENT treatment significantly improves and maintains CAR expression, thereby enhancing the cytotoxic activity of CAR-NK cells against CD138-positive multiple myeloma cells. ENT-treated CAR-NK cells exhibited prolonged persistence and more significant tumor reduction in an MM tumor-bearing mouse model, highlighting the therapeutic potential of HDACi-treated CAR-NK cells. This study provides the first evidence that HDAC inhibitors can sustain CAR expression in CAR-NK cells in a promoter-dependent manner, potentially enhancing anti-tumor efficacy in multiple myeloma and underscoring the possible need for further clinical evaluation.Copyright © 2025 Jo, Kaczmarek, Khan, Pervin, Clark, Gadde, Wang, McComb, Visram and Lee.
Age matters: A Secondary Analysis of Endothelial Biomarkers in the Prehospital Tranexamic Acid for Traumatic Brain Injury TrialAnand, Mcloud, Loss
et alJ Trauma Acute Care Surg (2025)
Abstract: Injured older adults account for nearly 25% of trauma admissions nationwide with increased morbidity and mortality compared with younger adults. Endothelial dysfunction has been associated with poor outcomes in trauma patients. We hypothesized that posttraumatic endothelial changes in older versus younger adult trauma patients will be different with worse outcomes in older adults.This is a retrospective secondary analysis of the "Tranexamic Acid (TXA) in Traumatic Brain Injury" prehospital database (2015-2017). We studied patients with admission endothelial biomarkers: intercellular adhesion molecule 1, angiotensin 1, thrombomodulin, vascular cell adhesion molecule 1 (VCAM 1), angiotensin 2, syndecan-1, and thrombospondin. We divided patients into age quartiles and compared the oldest quartile (older age [OA] group) with the three youngest quartiles (younger age [YA] group). In-hospital, discharge, and mortality outcomes were compared. Significance was set at p < 0.05.A total of 436 patients were included. The mean age in OA group was 66 years (55-88 years, n = 108). The YA mean age was 30 years (15-54 years, n = 328). There was no difference between OA and YA in rates of blunt trauma (98.1% vs. 96.3%, p = 0.61), head abbreviated injury scale (mean, 2.83 vs. 2.93; p = 0.582), or Injury Severity Score (mean, 21 vs. 19; p = 0.29). Tranexamic acid dosing was not different between cohorts (p = 0.571). Overall, the OA group had higher thrombomodulin (median, 693.3 vs. 592.9 pg/mL; p = 0.0008), VCAM 1 (median, 70,852 vs. 59,738 pg/mL; p = 0.0015), and angiotensin 2 (median, 165.3 vs. 134.2 pg/mL; p = 0.005). When comparing endothelial biomarkers of OA to each YA age quartile subsets, in the 2g TXA group OA patients had significantly higher syndecan-1 levels from a subset of YA (37 to 54-year-olds, p = 0.034). In the 2g TXA group OA patients had significantly lower plasma thrombomodulin, angiotensin 2, and VCAM 1 (p = 0.00001, p = 0.0032, and p = 0.0002, respectively) than patients in the placebo group. None of the biomarkers were independent predictors of 28-day mortality.Despite similar injury patterns, OA presented with higher admission endothelial plasma biomarkers. The OA patients receiving 2 g of TXA had significantly different endothelial biomarker levels versus YA group. These differences suggest that OA patients have a different baseline endothelial function prior to injury and that TXA may have a more pronounced effect on injured OA versus YA endothelium.Therapeutic Care Management; Level IV.Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.
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